Bisphosphonates (BP) have been used to halt bone loss and prevent osteoporosis-related fractures, but recent reports and our experience indicate that their long-term use may be related to atypical bone fractures. This poses a great public health concern because it could indicate a rising tide of difficult to treat, costly, atypical bone fractures now in the making. An understandable consequence of these reports is the growing mistrust from the public and physicians regarding use of BPs to treat bone loss. Thus, additional typical osteoporosis-related fractures could result due to reluctance to use BPs. This scenario, emanating from two different reasons for increasing fractures, creates an urgent need to clarify the relationship between long-term BP use and bone quality. Bone quality is important because it is widely regarded that alterations in this parameter are linked to bone fragility. The central hypothesis to be evaluated is that long-term BP use is associated with slow but progressive abnormalities in bone quality. The specific aims of the proposed study are to use an engineering-based approach to: 1) quantify bone quality abnormalities associated with no, short, medium, and long-term BP treatment and to evaluate the contributions of low bone turnover and/or osteoporosis as a disease per se, and 2) analyze the relationship between bone quality parameters and the continuous duration of BP use to determine the nature of these relationships (linear, second-order, exponential, etc.) with time. The availability of an unrivaled archive of bone biopsy specimens (8,000+) and the collaborative experience of our clinical, laboratory, and engineering-based research team offers the unique opportunity to efficiently achieve these specific aims. The proposed study will measure the microstructural, material, and mechanical parameters of cortical and cancellous bone quality in bone samples from: a) patients with osteoporosis or no, short, medium, and long-term BP therapy and b) healthy age-matched volunteers. These measurements will be made by using histomorphometry, Fourier Transform Infrared Spectroscopy, and nanoindentation. The proposed research offers a strong prospect to provide a substantial and sustained benefit to patients with osteoporosis. The findings will generate new information regarding the relationship between the duration of BP treatment and bone quality. If bone quality abnormalities are observed with BP treatment, then a basis will exist for reformulation of BP treatment guidelines. If no bone quality abnormalities are observed with BP treatment, then the findings will provide reassurance to patients and physicians allowing confident use of BPs. Thus, either outcome will provide valuable information regarding the therapeutic use of BPs. This will result in improved health for millions of patients with osteoporosis.